Head-to-Head Comparison of 68Ga-PSMA-11 PET/CT and Multiparametric MRI for Pelvic Lymph Node Staging Prior to Radical Prostatectomy in Patients With Intermediate to High-Risk Prostate Cancer: A Meta-Analysis

Purpose To compare the diagnostic performance of 68Ga-PSMA-11 PET/CT and mpMRI for pelvic lymph node staging prior to radical prostatectomy in prostate cancer (PCa) patients based on per patient data. Methods PubMed and Embase databases were searched until October 2020 for eligible studies evaluating head-to-head comparison of 68Ga-PSMA-PET/CT and mpMRI for the detection of pelvic lymph node metastases (PLNMs) using pelvic lymph node dissection (PLND) as gold standard. The pooled sensitivity, specificity, and area under the summary receiver-operating characteristics curve (AUC) were determined for the two imaging modalities. Results Nine studies with 640 patients were included. The pooled sensitivity, specificity, and AUC for 68Ga-PSMA-11 PET/CT vs. mpMRI were 0.71 (95% CI: 0.48–0.86) vs. 0.40 (95% CI: 0.16–0.71), 0.92 (95% CI: 0.88–0.95) vs. 0.92 (95% CI: 0.80–0.97), and 0.92 (95% CI: 0.88–0.95) vs. 0.82 (95% CI: 0.79–0.86), respectively. There was substantial heterogeneity for both imaging modalities, and meta-regression analysis revealed that the number of patients, prevalence of PLNMs, PSA level, reference standard, and risk classification might be the potential causes of heterogeneity. Conclusion This meta-analysis of head-to-head comparison studies confirms that there is a trend toward a higher sensitivity and diagnostic accuracy of 68Ga-PSMA-11 PET/CT compared to mpMRI for the detection of PLNMs in PCa patients. Nevertheless, according to current guidelines, PLND still needs to be recommended in case of negative results from 68Ga-PSMA-11 PET/CT due to significant risk of malignancy.


INTRODUCTION
Correct lymph node staging is crucial to identify prostate cancer (PCa) patients with poor prognosis who would benefit from additional therapies (1,2). Pelvic lymph node dissection (PLND) represents the gold standard, but it is impeded by increased risk of complications such as lymphedema and venous thromboembolism as well as longer hospital stay (3,4). Although cross-sectional abdominopelvic imaging has been recommended for patients with intermediate to high-risk PCa across guidelines, conventional imaging techniques only have modest diagnostic accuracy (4)(5)(6)(7).
In recent years, positron emission tomography (PET) techniques with PSMA ligands have emerged as a promising tool for PCa detection, tumor staging, and treatment planning (8). Among them, 68 Ga-PSMA-11 and 18 F-DCFPyL have been consecutively approved by the FDA for patients with primary and recurrent PCa (9,10). Nevertheless, although 18 F-based tracers offer important advantages such as higher production capacity, longer physical half-life, and minimal radiotracer accumulation in the bladder (11)(12)(13); up until now, 68 Ga-PSMA-11 is still worldwide the most commonly used and provides the absolute majority of evidence in the literature for PSMA imaging. Importantly, many accuracy studies and two previous meta-analyses have reported favorable diagnostic performance of 68 Ga-PSMA-11 PET/CT for the detection of pelvic lymph node metastases (PLNMs) in intermediate to high-risk PCa (14)(15)(16)(17).
Multiparametric MRI (mpMRI), which combines T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and dynamic contrast-enhanced (DCE) sequence, has been the leading imaging modality in the primary PCa detection and localization in the last decade. Several previous studies have compared it with 68 Ga-PSMA-11 PET/CT for pelvic lymph node staging prior to radical prostatectomy. However, the results were variable and sometimes conflicting (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Therefore, to clarify their relative effectiveness, in the present study, we sought to compare the diagnostic performance of these two imaging modalities by summarizing the most recent evidence in the literature. To reduce interstudy heterogeneity, only studies in which both modalities were performed in the same population were included.

MATERIAL AND METHODS
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (33).

Inclusion and Exclusion Criteria
Studies were eligible for inclusion if all the following criteria applied: (a) the diagnostic performance of 68 Ga-PSMA-11 PET/CT and mpMRI for pelvic lymph node staging prior to radical prostatectomy in PCa patients were clearly identified in the study or subset of the study; (b) the data were sufficient (i.e., patient number above 9) to construct a 2×2 contingency table; (c) the reference standard was histopathology confirmation from PLND, which should be clearly stated in the article. The exclusion criteria were (a) duplicated articles; (b) abstract, editorial comments, letters, case reports, review, or meta-analyses; and (c) clearly irrelevant titles and abstracts.
Using the aforementioned inclusion and exclusion criteria, two researchers independently screened titles and abstracts of the retrieved articles and then evaluated the full-text version of the remaining articles to determine their eligibility for inclusion. Disagreements between the researchers were resolved by consensus.

QUALITY ASSESSMENT
Two researchers independently assessed the quality of the included studies based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Each study was evaluated based on the following domains: patient selection, index test, reference standard, and flow and timing. These domains were then evaluated according to the risk of bias and were rated regarding applicability as "high," "low," or "unclear." Disagreements between the researchers were resolved by consensus.

Data Extraction
Two researchers independently conducted data extraction for all included articles. The extracted data included the first author, study characteristics (year, country, study design, prevalence of PLNMs, extracted lymph node number, and reference standard), patient characteristics (number of patients, age, PSA level, and D'Amico risk stratification), and technical aspects (field strength and MRI sequence for mpMRI; injection dose, uptake time, and image analysis for 68 Ga-PSMA-11 PET/CT). For each study, the absolute numbers of true-positive, true-negative, false-positive, and false-negative data for mpMRI and 68 Ga-PSMA-11 PET/CT were extracted on a per-patient basis. Disagreements between the researchers were resolved by consensus.

Statistical Analysis
The pooled sensitivity and specificity for 68 Ga-PSMA-11 PET/ CT and mpMRI were presented as estimates with 95% confidence intervals (CIs) by using random-effect analysis. The summary receiver-operating characteristic (SROC) curves were constructed, and the area under the curve (AUC) was calculated.

Literature Search and Study Selection
The initial search retrieved 414 articles, and 398 were excluded upon review of titles and abstracts. The remaining 16 articles were carefully assessed by full text, and another seven were excluded for the following reasons: insufficient reference standard (n = 2); data not retrievable for analysis (n = 2); not evaluated in the same patient population (n = 1); with only nodal-based data (n = 1); and tracers other than 68 Ga-PSMA-11 (n =1). Finally, nine articles including patient-based data on the head-to-head comparison of diagnostic performance of 68 Ga-PSMA-11 PET/CT and mpMRI were eligible for further analysis. A PRISMA flow diagram of the study selection process is shown in Figure 1.

Study Description and Quality Assessment
The study and patient characteristics of the nine articles comprising 640 patients are summarized in Table 1. The range of the prevalence of PLNMs for the included studies was 4% to 58.3%, and the median was 25%. The technical aspects of 68 Ga-PSMA-11 PET/CT and mpMRI were presented in Table 2.
Meta-regression analysis was performed to explore the sources of heterogeneity, and we identified that prevalence of PLNMs (p = 0.01 for specificity), PSA level (p < 0.001 for sensitivity and p < 0.001 for specificity), risk classification (p < 0.001 for sensitivity), and reference standard (p < 0.001 for specificity) were possible causes of heterogeneity for 68 Ga-PSMA-11 PET/CT. No publication bias was found (p = 0.15).
Meta-regression analysis revealed that number of patients (p < 0.001 for specificity) and PSA level (p < 0.001 for sensitivity) were possible causes of heterogeneity. No publication bias was found (p = 0.87).

DISCUSSION
The present meta-analysis pooled patient-based data from nine studies which compared 68 Ga-PSMA-11 PET/CT and mpMRI in the same population. It was found that the former had higher sensitivity (0.71 vs. 0.40), similar specificity (0.92 vs. 0.92), and higher AUC (0.92 vs. 0.82) as compared with the latter. The resulting relativeness was in agreement with those (sensitivity, 0.65 vs. 0.41; specificity, 0.94 vs. 0.92; AUC, 0.92 vs. 0.83) from a previous meta-analysis, in which indirect comparisons (not in the same population) were made by including 13 studies (29). The higher trend of sensitivity and diagnostic accuracy of 68 Ga-PSMA-11 PET/CT over mpMRI for pelvic lymph node staging prior to radical prostatectomy in patients with intermediate to high-risk PCa were thus confirmed based on the most recent evidence. To better illustrate the imaging features of mpMRI and 68Ga-PSMA PET/CT in characterizing lymph node metastases, an example of one patient who had underwent both imaging modalities was shown in Figure 5.
Different interpreting strategies for small PLNMs between the two imaging modalities across the included studies might help to explain the better performance of 68 Ga-PSMA-11 PET/ CT. While most of the mpMRI interpretations used the shortaxis diameter of more than 10 or 8 mm as a determining factor for malignancy, all PET/CT interpretations decided PLNMs solely based on PSMA uptake, irrespective of the small size of lymph nodes. Thus, some small PLNMs without significant  (32). Nevertheless, 68 Ga-PSMA-11 PET/CT still missed as many as 29% of the PLNMs identified by PLND according to the result of our meta-analysis. In a study of 140 patients, Van Leeuwen et al. reported that no lymph nodes detected < 2 mm and only 27% of the lymph node metastases 2 and 4 mm were detected by preoperative 68 Ga-PSMA-PET/CT (24). In a larger study of 208 patients, Yaxley et al. found that 85.4% of histologically positive LNs ≤ 5 mm in maximal diameter were missed by preoperative 68 Ga-PSMA PET/CT (34). It seems that the resolution of 68 Ga-PSMA PET/CT is still not sufficient to detect many microscopic diseases seen at histopathology, particularly those with a diameter <5 mm. However, since it has been reported that the presence of microscopic diseases is associated with late disease recurrence, similar to PLNMs with large diameter, the clinical impact of these radiographically undetected microscopic diseases could be significant (35,36). Therefore, despite its known limitations and complications, PLND remains necessary in that it could reveal microscopic diseases that might lead to early initiation of salvage radiotherapy and androgen deprivation therapy, which would eventually result in improved long-term local pelvic control and improved biochemical-free progression (2,37). On the other hand, according to the current EAU or NCCN guidelines, if the risk of a PLNM is >5% or >2%, respectively, PLND is recommended at the time of radical prostatectomy (38,39). Based on the results of this meta-analysis, Fagan's nomogram indicated that when the pretest probability (prevalence of PLNMs) was assumed to be 25%, which is the medium value of our included studies, the negative posttest probability (the probability of being malignancy when the test is negative) decreased to 10% for 68 Ga-PSMA-11 PET/CT and 22% for mpMRI ( Figure 6). Thus, negative test results from both imaging modalities leaves a residual malignancy risk of above 5%. In this regard, PLND still needs to be recommended if 68 Ga-PSMA PET/CT or mpMRI did not identify any suspicious lymph nodes.
In recent years, researchers have begun to incorporate 68 Ga-PSMA PET/CT and mpMRI parameters into comprehensive preoperative algorithms to evaluate the risk of PLNMs. Franklin et al. found that the combination of a negative 68 Ga-PSMA PET/ CT, ISUP biopsy grade <4 and PIRADS <4 prostate mpMRI, or an ISUP grade 5 with PIRADS <3 on mpMRI was associated with a <5% risk of PLNMs (32). Ferraro et al. devised a model based on visual lymph node status on 68 Ga-PSMA PET/CT, total PSMA uptake of the primary tumor, PSA, and Gleason score, which showed a tendency to improve patient selection for PLND overprediction models using clinical risk factors (40). It is hoped that future nomograms incorporating not only clinical risk   factors but also data from modern imaging modalities will help to more appropriately select candidates for PLND. Moreover, hybrid PET/MRI modality may offer incremental value for preoperative detection of PLNMs. In a 2018 study, Thalgott et al. demonstrated that 68 Ga-PSMA-11 PET/MRI even had a specificity of 100% in this setting (41).
Major limitations of our study include small sample size and heterogeneous study and patient characteristics and technical aspects of the included studies. We tried our best to perform subgroup analyses and found that number of patients, prevalence of PLNMs, PSA level, reference standard, and risk classification might be the sources of heterogeneity for the two imaging modalities. Besides, we only analyzed patient-based data in the present meta-analysis, because in clinical practice, it is difficult to precisely associate either PET or MRI findings with the histological results in a node-to-node manner and patients with one positive PLNM could provide enough prognostic information to alter patient management (34).
In conclusion, this meta-analysis of head-to-head comparison studies confirms that there is a trend toward a higher sensitivity and diagnostic accuracy of 68 Ga-PSMA-11 PET/CT compared to mpMRI for the detection of PLNMs in PCa patients.
Nevertheless, according to current guidelines, PLND still needs to be recommended in case of negative results from 68 Ga-PSMA-11 PET/CT due to significant risk of malignancy. Hybrid PET/ MRI modality exploiting both the superb molecular information from 68 Ga-PSMA-11 PET and the high local contrast of MRI may represent a future direction.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.